It all depends on whose side you're on. The worst trade ever for one team is naturally going to be the best damn trade ever for the other team. So let's call this The Most Lopsided Trade of All Time.
If asked, many knowledgeable NFL fans would go with the infamous Herschel Walker trade. On Oct. 12, 1989, the Vikings gave the Cowboys five players, six conditional draft choices and a 1992 first-round pick, in exchange for Walker and a 4th round pick. Ultimately, after all their wheeling and dealing was done, Dallas essentially wound up with Emmitt Smith, Darren Woodson, Russell Maryland, Kevin Smith, and Clayton Holmes. Minnesota ended up with Walker and Jake Reed. Walker played 2.5 seasons for Minnesota, he was ok but not great, and the team did not improve. The guys Dallas got of course helped them win three Super Bowls. So Minnesota got smoked but I'd say the deal was at least somewhat defensible. Minnesota was a playoff team with mediocre running backs and Walker was coming off two fine seasons at the time of the deal. The Vikings could reasonably believe they were one good RB away from the Super Bowl and that Walker might be that back. He wasn't but it's not like the coach changed his offense around to feature him. After all, why the hell would you want to do that with the guy you just sacrificed your team's future for? At least Herschel gave them some production while Jake Reed had several very good years for them.
Probably the other most famous lopsided NFL trade was in 1983 when the Colts traded John Elway to Denver in exchange for QB Mark Hermann, OT Chris Hinton and a 1984 1st-rounder which Indy used to take G Ron Solt. Okay, trading away a future all-time great pretty much guarantees disaster but look it at from the Colts point of view. Elway said he wouldn't play for them, he was going to go play baseball. The Colts didn't have much choice after Elway, setting the stage for Eli Manning two decades later, stamped his tiny feet and threatened to take his ball and go home if he didn't get dealt. The Colts salvaged something out of the pick at least. Hinton was a 5-time all-pro and Solt had a solid 9-year career (Hermann was a bust).
To me, neither of those trades compares with my candidate for the Most Lopsided Trade of All Time. My choice was totally indefensible at the time it was made and the team that made it didn't get jack out of it. Seven games into the 1974 season, the Green Packers gave up two 1st round picks, two second round picks, and a third round pick to the Rams in exchange for QB John Hadl. Now Hadl was coming off his best season but he was 34 and playing absolutely horribly at the time of the trade. He continued to play horribly after the trade and in 1975 he threw 6 TD's and 21 INT's and was gone after the season. A complete bust for the Pack. On the other hand, with the 1975 picks they received the Rams got DT Mike Fanning (solid 10-year vet), DB Monte Jackson (two-time Pro Bowler), and C Geoff Reece who they traded the next year for a 2d round pick they used to take for DB Nolan Cromwell (four-time Pro Bowler). In 1976, they got DB Pat Thomas (two-time All Pro), and traded away the first rounder for WR Ron Jessie (who made a Pro Bowl with the Rams). The Rams got 5 high-quality players who helped them their division for the next 5 years straight. The Pack got a washed-up quarterback.
To this day nobody has anybody what Dan Devine was thinking (or smoking) when he made that deal. Green Bay was a below average team with lots of holes, holes they couldn't possibly fill by trading away all those picks. Hadl was 34 years old and the Rams had already benched him at time of the deal. And you give up FIVE high picks for him?!?!?! That, is the worst, the stupidest, the most lopsided trade of all time.
Often times, bad deals have further repurcussions that make the initial deal even worse than it already was. To try to mitigate some of the damage and replace some of the lost picks, after the '74 season the Pack traded away LB Ted Hendricks to the Raiders for two first round picks. The Packers used them to snag DL Ezra Johnson (who had a solid career) and T Mike Koncar (a bust). Meanwhile, Hendricks played 9 more years, made 4 Pro Bowls with the Raiders, played on 3 Championship teams, and went on to the Hall of Fame.